P543: TARGETING SAMHD1 WITH HYDROXYUREA IN FIRST-LINE CYTARABINE-BASED THERAPY OF NEWLY DIAGNOSED ACUTE MYELOID LEUKAEMIA: RESULTS FROM THE HEAT-AML TRIAL
Authors: M. Jädersten, I. Lilienthal, N. Tsesmetzis, M. Lourda, S. Bengtzén, A. Bohlin, C. Arnroth, T. Erkers, B. Seashore-Ludlow, G. Giraud, G. S. Barkhordar, S. Tao, L. Fogelstrand, L. Saft, P. Östling, R. Schinazi, B. Kim, T. Schaller, G. Juliusson, S. Deneberg, S. Lehmann, G. Rassidakis, M. Höglund, J.-I. Henter, N. Herold
Journal: HemaSphere (2022)

Background: Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-CTP levels through targeted inhibition of SAMHD1. Aims: To evaluate feasibility, safety, and efficacy of adding hydroxyurea to standard AML-directed therapy according to national guidelines. To perform translational studies including SAMHD1-staining on bone marrow sections, pharmacokinetics and drug-sensitivity analysis on leukemic cells ex vivo. Methods: This phase-1 trial (EudraCT-number: 2018-004050-16) was run at two sites (Karolinska University Hospital and Uppsala University Hospital, Sweden). Eligibility criteria included age >18 years, newly diagnosed non-promyelocytic AML, and fitness for intensive chemotherapy. Patients with CBF-AML eligible for treatment with gemtuzumab-ozogamicin were excluded. Treatment comprised 2 to 4 cycles of ara-C 1000 mg/m2 i.v. b.i.d. on day 1-5 during all 4 cycles and daunorubicin 60 mg/m2 i.v. q.d. on day 1-3 during cycles 1 and 2, and on day 1-2 during cycle 3. Patients with FLT3-mutated AML received midostaurin 50 mg b.i.d. on day 8-21 of each cycle. Risk-adapted allo-HSCT was performed at the discretion of the treating haematologist. The dose of hydroxyurea was escalated in a 3 + 3 design: 500 + 500 mg (level 1), 1000 + 500 mg (level 2), and 1000 + 1000 mg (level 3), each dose being given 1 hour prior to start of the ara-C infusion b.i.d. on day 1-5. Here we report the results of the first 9 patients in the run-in phase 1 part of the study. The phase 2 part will include an additional 60 patients. Recruitment is ongoing, utilizing the highest dose of hydroxyurea. Expression of SAMHD1 was assessed using a double-immunostaining method (SAMHD1/CD68), an autostainer system (BenchMark Ultra, Ventana, Rotkreuz, Switzerland) and previously validated protocols20. CD68+/SAMHD1+ histiocytes (macrophages) served as internal controls in all bone marrow biopsies assessed. Drug sensitivity analysis was performed on AML mononuclear cells utilized a high-throughput system evaluating >500 cytotoxic agents including combinations of ara-C and hydroxyurea in different doses. Results: All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow-cytometry or RT-qPCR) had an MRD level <0.1% after two cycles of chemotherapy. Six of nine patients underwent hematopoietic stem cell transplantation. With a median follow-up of 13.2 months, no relapse has been observed. No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in ara-CTP levels (1.5-fold; P=0.04) in the 6 patients receiving single doses of 1000 mg hydroxyurea. Drug-sensitivity analysis indicated an additive effect of ara-C and hydroxyurea on leukemic cells ex vivo. There was no apparent correlation between expression of SAMHD1-expression and efficacy; all patients had deep responses. Image:Summary/Conclusion: The high rate of complete remission and MRD negativity together with the pharmacokinetic and ex vivo evidence suggest that the efficacy of cytarabine-based AML treatment can be enhanced by addition of hydroxyurea as a targeted inhibitor of SAMHD1. Importantly, orally administered hydroxyurea may provide a safe, inexpensive, and broadly accessible strategy to improve outcome in AML. These results will have to be validated in a larger patient cohort.